Affinage

PHF8

Histone lysine demethylase PHF8 · UniProt Q9UPP1

Length
1060 aa
Mass
117.9 kDa
Annotated
2026-06-10
90 papers in source corpus 45 papers cited in narrative 46 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 7/7 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

PHF8 is a nuclear Fe(II)/2-oxoglutarate-dependent JmjC-domain histone lysine demethylase whose N-terminal PHD finger reads active H3K4me2/3 marks to target the enzyme to transcription start sites, where its catalytic domain erases the repressive marks H3K9me1/2 and H4K20me1 to activate transcription (PMID:20622854, PMID:20622853, PMID:20346720, PMID:20421419). Structural and enzymatic work defines a double-stranded beta-helix JmjC fold with conserved Fe(II)/2-OG sites that selects di- and mono-methylated substrates over the trimethyl state, and shows that clinical JmjC mutations such as F279S abolish demethylase activity and the gene's regulatory functions, linking PHF8 to an X-linked intellectual disability syndrome with cleft lip/palate (PMID:20208542, PMID:19843542, PMID:20101266, PMID:20067792). Through this read-and-erase mechanism PHF8 functions as a transcriptional coactivator that physically engages the RNAPII C-terminal domain and nuclear receptors RARα and AR, and promotes G1-S and G2/M cell cycle progression by demethylating H4K20me1 at E2F-regulated promoters and H3K9me2 at cyclin loci; its dismissal from chromatin in prophase permits H4K20me1 accumulation for condensin II loading (PMID:20622854, PMID:20548336, PMID:20421419, PMID:25548279). PHF8 also drives rRNA transcription at hypomethylated rDNA promoters in the nucleolus in concert with RNA Pol I and WDR5-containing H3K4 methyltransferase complexes, antagonized there by PHF2-SUV39H1 and KDM2A (PMID:20208542, PMID:20531378, PMID:25204660, PMID:40427554). PHF8 abundance and activity are tightly controlled: it is phosphorylated by cyclin E-CDK2, ERK2 and CK2, ubiquitinated for mitotic degradation by APC-CDC20 and by NEDD4L, and stabilized by USP7 in a feedback loop required for DNA damage repair (PMID:23979597, PMID:25548279, PMID:33010150, PMID:28100697, PMID:27183383, PMID:36136271). Beyond histones, PHF8 demethylates non-histone substrates to act in the replication-stress and DNA-damage response — demethylating TOPBP1 to promote RAD9 loading and ATR activation, reversing DYRK1B-EHMT2-deposited H3K9me2 at double-strand breaks to restart transcription, demethylating RNF113A to limit ASCC-dependent alkylation repair, and co-repressing electron-transport-chain genes via demethylation of YY1 to control mitochondrial ROS (PMID:33952527, PMID:39087553, PMID:41509214, PMID:38165927). Across development and disease PHF8 regulates neuronal differentiation, axon guidance, synapse formation, mTOR signaling, serine-biosynthesis-driven neural progenitor proliferation, and acts as an oncogenic driver in prostate, breast, gastric, renal, melanoma and other cancers through transcriptional programs including HIF/AR, MYC, TGF-β/SNAI1 and FOXA2 (PMID:22850744, PMID:29317619, PMID:27899639, PMID:27991916, PMID:33009820, PMID:41714361).

Mechanistic history

Synthesis pass · year-by-year structured walk · 11 steps
  1. 2009 High

    Established that PHF8 is a catalytically active enzyme, answering whether the JmjC protein is a bona fide demethylase and whether disease mutations impair catalysis.

    Evidence In vitro enzymatic assay with recombinant protein on peptide and intact histone substrates plus F279S mutagenesis

    PMID:19843542

    Open questions at the time
    • Cellular targets and genomic localization not addressed
    • Substrate preference among H3K9/H4K20 marks not fully resolved here
  2. 2010 High

    Defined PHF8 substrate specificity and the structural basis for its di-/mono-methyl selectivity, explaining why patient JmjC mutations are loss-of-function.

    Evidence X-ray crystallography of the catalytic core with Fe(II)/2-OG sites and demethylation assays/mutagenesis

    PMID:20067792 PMID:20101266

    Open questions at the time
    • Structure of the full-length protein including PHD-JmjC arrangement not determined
    • Conformational regulation by partners/PTMs not captured
  3. 2010 High

    Connected the PHD reader to function, showing PHF8 PHD binds H3K4me2/3 to recruit the enzyme to active promoters and that this coupling drives transcriptional coactivation.

    Evidence PHD peptide-binding assays, ChIP-Seq mapping to TSS, Co-IP with RNAPII-CTD and RARα, reporter assays

    PMID:20346720 PMID:20421419 PMID:20548336 PMID:20622853

    Open questions at the time
    • Quantitative contribution of reader vs catalytic activity to each target gene unresolved
    • Genome-wide partner repertoire incomplete
  4. 2010 High

    Placed PHF8 in cell cycle and rRNA control, showing H4K20me1 demethylation at E2F1 promoters drives G1-S and H3K9me1/2 demethylation at rDNA drives rRNA transcription.

    Evidence ChIP-Seq, in vitro demethylase assays, cell cycle synchronization, nucleolar co-localization with B23/fibrillarin, mutagenesis (H247A)

    PMID:20208542 PMID:20531378 PMID:20622854

    Open questions at the time
    • Mechanism of phosphorylation-dependent chromatin dismissal in prophase only partially defined
    • Direct vs indirect E2F target distinction incomplete
  5. 2013 High

    Revealed cell-cycle-coupled turnover of PHF8, answering how its activity is restricted to specific phases via ubiquitin-dependent degradation.

    Evidence Protein complex purification, in vitro/in vivo ubiquitination with APC-CDC20, LXPKXLF motif mutagenesis, cell cycle analysis

    PMID:23979597

    Open questions at the time
    • Upstream signals timing APC-CDC20 engagement not fully mapped
    • Interplay with stabilizing pathways not addressed here
  6. 2014 High

    Defined kinase regulation of PHF8 demethylase activity, showing cyclin E-CDK2 phosphorylation at Ser844 enhances H3K9me2 removal and S-phase gene transcription.

    Evidence MS phosphosite identification, kinase assays, ChIP, reporter assays, S844A mutant

    PMID:25548279

    Open questions at the time
    • Structural effect of phosphorylation on the catalytic domain unknown
    • Crosstalk with ERK2/CK2 phosphosites not integrated
  7. 2016 High

    Identified deubiquitination as a stabilizing axis, showing USP7 protects PHF8 from degradation in a feedback loop that supports target gene expression and DSB repair.

    Evidence Reciprocal Co-IP, ubiquitination assays, ChIP, functional rescue and tumor models

    PMID:27183383

    Open questions at the time
    • Balance between USP7 stabilization and APC/NEDD4L degradation not quantitatively resolved
    • Direct DSB demethylase substrates not defined here
  8. 2017 High

    Established signal-responsive eviction of PHF8 from corepressor-bound promoters, showing ERK2 phosphorylation and partnership with SIN3A/HDAC1 govern IFNγ gene induction.

    Evidence Affinity purification/MS partner identification, Co-IP, ChIP, ERK2 kinase assay, siRNA

    PMID:28100697

    Open questions at the time
    • Generality of the eviction model across other stimuli untested
    • Direct vs scaffolded role within SIN3A/HDAC1 complex unclear
  9. 2021 High

    Demonstrated a non-histone demethylase function in the replication-stress response, showing PHF8 demethylates TOPBP1-K118 to gate RAD9 loading and ATR activation.

    Evidence In vitro demethylase assay on non-histone substrate, Co-IP, phosphorylation/dissociation assays, ChIP, genetic rescue

    PMID:33952527

    Open questions at the time
    • Methyltransferase that deposits TOPBP1-K118me not identified here
    • Relationship to CK2-dependent TOPBP1 stabilization not unified
  10. 2024 High

    Expanded the non-histone substrate repertoire to metabolic control, showing PHF8 demethylates YY1 to co-repress ETC genes and drive mitochondrial ROS and cancer growth, with a tractable inhibitor.

    Evidence Non-histone demethylase assay on YY1, specific inhibitor iPHF8, ChIP, gene expression, xenograft/PDX

    PMID:38165927

    Open questions at the time
    • YY1 methylation site and writer enzyme detail limited
    • Tissue specificity of the YY1-ETC axis untested broadly
  11. 2026 Medium

    Linked PHF8 to metabolic programming in development, showing it sustains serine biosynthesis and chromatin accessibility at metabolic gene promoters for neural progenitor proliferation.

    Evidence Multi-omics integration with conditional Phf8 KO mice, ChIP, metabolomics

    PMID:41714361

    Open questions at the time
    • Direct demethylase targets among metabolic promoters not fully resolved
    • Causal ordering of metabolic vs DNA-damage phenotypes unclear

Open questions

Synthesis pass · forward-looking unresolved questions
  • How PHF8's catalytic, scaffolding (demethylase-independent SETDB1 degradation), reader, and non-histone activities are coordinated by its PTM code (CDK2/ERK2/CK2 phosphorylation, SUMOylation, ubiquitination) into context-specific outcomes remains unresolved.
  • No unified structural model integrating PHD reader, JmjC catalysis, and IDR-mediated partner binding
  • Rules determining histone vs non-histone substrate choice in vivo undefined
  • Full PTM hierarchy controlling activity vs stability not mapped

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0016491 oxidoreductase activity 3 GO:0042393 histone binding 3 GO:0140096 catalytic activity, acting on a protein 3 GO:0140110 transcription regulator activity 3
Localization
GO:0005634 nucleus 2 GO:0005730 nucleolus 2 GO:0000228 nuclear chromosome 1
Pathway
R-HSA-1266738 Developmental Biology 4 R-HSA-1643685 Disease 4 R-HSA-1640170 Cell Cycle 3 R-HSA-4839726 Chromatin organization 3 R-HSA-73894 DNA Repair 3 R-HSA-74160 Gene expression (Transcription) 3
Partners
ARCDC20KDM2ARARATOPBP1USP7YY1ZNF711

Evidence

Reading pass · 46 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2010 PHF8 functions as an H4K20me1 demethylase (in addition to H3K9me1/2 and H3K27me2 substrates). Its PHD domain binds H3K4me2/3 and recruits PHF8 to promoters. PHF8 controls G1-S transition with E2F1, HCF-1, and SET1A by removing repressive H4K20me1 from E2F1-regulated gene promoters. Phosphorylation-dependent dismissal of PHF8 from chromatin in prophase allows H4K20me1 accumulation during early mitosis, facilitating condensin II (N-CAPD3 and N-CAPG2 recognize H4K20me1) loading. In vitro demethylase assays, Co-IP, ChIP-Seq, mass spectrometry, cell cycle synchronization experiments, phosphorylation studies Nature High 20622854
2010 PHF8 is the first identified H4K20me1 demethylase, with additional activities toward H3K9me1 and H3K9me2. PHF8 PHD domain binds H3K4me3 and is required for catalytic activity and gene regulation. Patient mutations in the JmjC domain significantly compromise PHF8 catalytic function. PHF8 regulates zebrafish neuronal cell survival and jaw development partly by directly regulating MSX1/MSXB expression. In vitro demethylase assays, PHD-H3K4me3 binding assays, ChIP, morpholino knockdown in zebrafish, patient mutation analysis Nature High 20622853
2010 PHF8 associates with hypomethylated rDNA and interacts with the RNA Pol I transcription machinery and WDR5-containing H3K4 methyltransferase complexes. PHF8 demethylates H3K9me1/2 at rDNA promoters, and its catalytic activity is stimulated by adjacent H3K4me3. A JmjC point mutation (linked to mental retardation with cleft lip/palate) abolishes demethylase activity and transcriptional activation of rRNA genes. Co-IP, ChIP, in vitro demethylase assays, reporter assays, mutagenesis Nature structural & molecular biology High 20208542
2010 PHF8 catalyzes demethylation of H3K9me2/me1. The PHD domain of PHF8 binds H3K4me3 and colocalizes with H3K4me3 at transcription initiation sites. PHF8 physically interacts with XLMR protein ZNF711, which binds to a subset of PHF8 target genes including JARID1C. In vitro demethylase assays, PHD binding assays, Co-IP, ChIP Molecular cell High 20346720
2009 Recombinant PHF8 is an Fe(II) and 2-oxoglutarate-dependent Nε-methyl lysine demethylase acting on histone substrates, selective for di- and mono-methylated lysine residues (not trimethyl). The clinically observed F279S variant within the double-stranded beta-helix fold is catalytically inactive on both peptide and intact histone substrates. In vitro enzymatic assay with recombinant protein, mutagenesis (F279S variant), peptide and intact histone substrates Human molecular genetics High 19843542
2010 Crystal structure of the PHF8 catalytic core reveals a double-stranded beta-helix fold with conserved Fe(II) and 2-oxoglutarate binding sites. PHF8 is selective for H3K9me2/1 but not H3K9me3. Structural basis for discrimination between methylation states and sequence specificity for methylated H3K9 is defined. The F279S patient mutation abolishes demethylation activity. X-ray crystallography, in vitro demethylation assay, mutagenesis Cell research High 20101266
2010 Crystal structure of the PHF8 JmjC domain reveals a double-stranded beta-helix fold with conserved Fe(II) and cosubstrate binding sites typical of 2-oxoglutarate-dependent oxygenases. The active site is conserved with FBXL10/11 demethylases (di-/mono-methyl selective) but differs from JMJD2 demethylases (tri-/di-methyl selective). Results rationalize loss of activity in the F279S clinical variant. X-ray crystallography, structural comparison FEBS letters High 20067792
2010 PHF8 is a histone demethylase that removes H3K9me2 marks (H3K9me1/2 in vitro). Its PHD finger domain binds specifically to H3K4me3/2 peptides. PHF8 acts as a transcriptional coactivator for RARα and promotes RA-induced neuronal differentiation of P19 cells. The F279S disease mutant is defective in enzymatic activity and fails to drive neuronal differentiation. In vitro demethylase assay, PHD peptide binding assay, Co-IP (PHF8-RARα), neuronal differentiation assay, mutagenesis Cell research High 20548336
2010 PHF8 is a histone demethylase for H3K9me2 localized in the nucleolus (co-localizing with B23 and fibrillarin). PHF8 binds the rDNA promoter and positively regulates rRNA transcription. The catalytically inactive H247A mutant (conserved histidine to alanine) abolishes demethylase activity and fails to upregulate rRNA transcription. In vitro demethylase assay, mutagenesis (H247A), immunofluorescence co-localization, ChIP, knockdown/overexpression assays Cell research High 20531378
2010 PHF8 PHD domain specifically associates with H3K4me3. PHF8 is enriched at transcription start sites of active/poised genes mirroring RNAPII and H3K4me3. PHF8 directly interacts with the C-terminal domain of RNAPII. PHF8 acts as a transcriptional coactivator and its activation function largely depends on PHD binding to H3K4me3. A disease mutant is defective in demethylation and coactivation. Biochemical PHD binding assay, ChIP-Seq, Co-IP (PHF8-RNAPII CTD), reporter assay, mutagenesis Molecular and cellular biology High 20421419
2016 PHF8 physically associates with deubiquitinase USP7. USP7 promotes deubiquitination and stabilization of PHF8, leading to upregulation of PHF8 target genes including cyclin A2. USP7 transcription is itself positively regulated by PHF8, forming a positive feedback loop. The USP7-PHF8 interaction is augmented during DNA damage; PHF8 stabilization by USP7 is required for recruitment of BLM and KU70 for DSB repair. Co-IP, ubiquitination assay, ChIP, knockdown/overexpression, in vivo tumor models The Journal of clinical investigation High 27183383
2013 PHF8 protein levels peak during G2 phase and mitosis and are regulated by the ubiquitin-proteasome system. PHF8 interacts with the CDC20-containing APC (APC-CDC20) primarily during mitosis. A novel LXPKXLF motif on PHF8 (KEN- and D-box-independent) is required for binding to CDC20; mutations of this motif abrogate polyubiquitylation of PHF8 by APC. Loss of PHF8 leads to prolonged G2 phase and defective mitosis. Protein complex purification, Co-IP, in vitro/in vivo ubiquitination assays, mutagenesis, cell cycle analysis Molecular and cellular biology High 23979597
2014 Cyclin E-CDK2 phosphorylates PHF8 at Ser-844. Phosphorylation by cyclin E-CDK2 enhances PHF8 demethylase activity toward H3K9me2 and promotes S-phase progression. Phosphorylation-deficient PHF8-S844A mutant is less efficient at binding cyclin E promoter and demethylating H3K9me2 there, resulting in reduced transcription of cyclin E, E2F3, and E2F7, and reduced rRNA transcription. Mass spectrometry (substrate identification), kinase assay, immunoblot, flow cytometry, ChIP, luciferase reporter, mutagenesis The Journal of biological chemistry High 25548279
2021 PHF8 interacts with and demethylates TOPBP1 at K118 mono-methylation under unperturbed conditions. Replication stress causes PHF8 phosphorylation and dissociation from TOPBP1. Hypomethylated TOPBP1 facilitates RAD9 binding and chromatin loading of the TOPBP1-RAD9 complex to fully activate ATR kinase, safeguarding the genome against replication stress. Co-IP, in vitro demethylase assay (non-histone substrate), phosphorylation assays, ChIP, genetic rescue experiments Science advances High 33952527
2020 CK2 kinase phosphorylates PHF8 at Ser854, and this phosphorylation mediates binding of PHF8 to the BRCT 7+8 domain of TopBP1. PHF8 prevents ubiquitination and degradation of TopBP1 by the E3 ligase UBR5, thereby stabilizing TopBP1 protein levels and regulating DNA replication checkpoint and replication fork restart. Co-IP, kinase assay, ubiquitination assay, mutagenesis, cell cycle analysis Nucleic acids research High 33010150
2013 PHF8 functions as a transcriptional coactivator specifically recruited by RARα fusions (PML-RARα) upon ATRA treatment in APL. ATRA sensitivity depends on both the enzymatic (demethylase) activity and the phosphorylation status of PHF8. Forced PHF8 expression resensitizes ATRA-resistant APL cells; PHF8 downregulation confers resistance. Co-IP (PHF8-RARα fusion), ChIP, knockdown/overexpression, ATRA treatment, pharmacological manipulation of PHF8 phosphorylation Cancer cell High 23518351
2012 PHF8 directly regulates expression of cytoskeleton/cell adhesion genes RhoA, Rac1, and GSK3β by demethylating H4K20me1 at their promoters. c-Myc transcription factor cooperates with PHF8 to regulate these promoters. PHF8 depletion results in disorganized actin cytoskeleton, impaired cell adhesion, and deficient neurite outgrowth. ChIP, H4K20me1 demethylase assay, siRNA knockdown, cytoskeletal imaging, neurite outgrowth assay Nucleic acids research Medium 22850744
2017 PHF8 is recruited to IFNγ-responsive promoters prior to stimulation and, through association with HDAC1 and SIN3A corepressors (identified by affinity purification/mass spectrometry), keeps promoters silent by maintaining low H4K20me1 levels. Upon IFNγ treatment, PHF8 is phosphorylated by ERK2 and evicted from promoters, correlating with H4K20me1 increase and transcriptional activation. Affinity purification/mass spectrometry (SIN3A/HDAC1 partners), Co-IP, ChIP, ERK2 kinase assay, siRNA knockdown Nucleic acids research High 28100697
2017 PHF8 PHD domain depletion results in H3K4me3 loss at promoters of hypoxia-inducible genes (including KDM3A). PHF8 regulates hypoxia signaling mainly by sustaining H3K4me3 levels. PHF8 cooperates with KDM3A to regulate neuroendocrine differentiation genes under hypoxia. PHF8 role in hypoxia signaling is associated with presence of full-length AR in CRPC cells. CRISPR-Cas9 KO, RNAi knockdown, ChIP, gene expression analysis Biochimica et biophysica acta. Gene regulatory mechanisms Medium 28734980
2017 PIP2 (phosphatidylinositol-4,5-bisphosphate) directly interacts with PHF8 via a C-terminal K/R-rich motif and represses H3K9me2 demethylation by PHF8. PIP2-binding mutant PHF8 has increased rDNA promoter activity (20%) and pre-rRNA gene expression (47S-100%; 45S-66%). PIP2 binding may induce a conformational change in PHF8. Direct binding assay (PIP2-PHF8), mutagenesis of K/R-rich motif, reporter assay, RT-PCR, trypsin protection assay Biochimica et biophysica acta. Molecular and cell biology of lipids Medium 29246768
2018 In Phf8 knockout mice, mTOR signaling is hyperactive in hippocampus. Mechanistically, demethylation of H4K20me1 by Phf8 results in transcriptional suppression of RSK1, maintaining mTOR signaling homeostasis. Pharmacological suppression of mTOR signaling with rapamycin in Phf8 KO mice recovers impaired LTP and cognitive deficits. Phf8 KO mice, ChIP, gene expression analysis, rapamycin pharmacological rescue, LTP electrophysiology Nature communications High 29317619
2017 PHF8 promotes EMT and breast cancer development by demethylating H3K9me1/H3K9me2 and sustaining H3K4me3 to prime transcriptional activation of SNAI1 by TGF-β signaling. PHF8 is post-transcriptionally regulated by MYC through repression of miR-22, which directly targets PHF8. This MYC/miR-22/PHF8 axis places PHF8 as a downstream effector of MYC. ChIP, gene expression analysis, miRNA reporter assay, knockdown/overexpression, genome-wide expression analysis Nucleic acids research Medium 27899639
2016 PHF8 interacts with and functions as a histone demethylase activity-dependent coactivator of androgen receptor (AR). PHF8 expression is induced by hypoxia via HIF1α and HIF2α (knockdown of either almost completely abolished hypoxia-induced PHF8 expression). Thus the HIF/PHF8/AR signaling axis promotes AR-driven prostate cancer progression. Co-IP (PHF8-AR), siRNA knockdown of HIF1α/HIF2α, ChIP, gene expression analysis Oncogenesis Medium 27991916
2014 PHF2 antagonizes PHF8 at rDNA promoters by competing for H3K4me2/3 binding and recruiting H3K9me2/3 methyltransferase SUV39H1. Simultaneous depletion of both PHF8 and PHF2 restores rDNA transcription to baseline levels, demonstrating opposing roles in rDNA regulation. Epistasis by double siRNA knockdown, ChIP, Co-IP (PHF2-SUV39H1), reporter assays, binding assays The Journal of biological chemistry Medium 25204660
2017 PHF8 directly identifies serotonin receptor genes Htr1a and Htr2a as target genes in prefrontal cortex. Phf8 knockout mice show misregulation of serotonin signaling and striking resilience to stress-induced anxiety- and depression-like behavior. Phf8 KO mice, ChIP (PHF8 at Htr1a/Htr2a promoters), behavioral assays, gene expression analysis Nature communications Medium 28485378
2016 In LPS-activated macrophages, PHF8 knockdown reduces pro-inflammatory gene transcription and increases H3K9me2 written by G9a methyltransferase. PHF8 promotes T-cell activation and proliferation. PHF8 opposes G9a-mediated H3K9me1/2 writing to activate specific secreted proteins that are suppressed in endotoxin-tolerant cells. siRNA knockdown, ChIP, quantitative secretome analysis, T-cell proliferation assay, epistasis with G9a Scientific reports Medium 27112199
2019 PHF8 interacts with β-catenin and binds to the promoter region of vimentin, promoting vimentin transcription. H. pylori markedly induces PHF8 expression in gastric cancer. PHF8-β-catenin-vimentin axis is activated in gastric cancer malignant progression. Co-IP (PHF8-β-catenin), ChIP (PHF8 at vimentin promoter), knockdown/overexpression American journal of cancer research Medium 28401003
2016 PHF8 controls E2F4 expression in endothelial cells by reducing H3K9me2 levels at the E2F4 transcriptional start site, as demonstrated by ChIP. PHF8 knockdown impairs endothelial cell migration and tube formation. PHF8 does not control E2F1 expression in endothelial cells. ChIP (PHF8 and H3K9me2 at E2F4 TSS), siRNA knockdown, migration and tube formation assays PloS one Medium 26751588
2022 PHF8 inhibition elicits H3K9me3-dependent retrotransposon activation by promoting proteasomal degradation of H3K9 methyltransferase SETDB1 in a demethylase-independent manner. PHF8 ablation stimulates a viral mimicry response in colorectal cancer cells, activating innate immune signaling and anti-tumor immunity. CRISPR KO, proteasome inhibitor experiments, ChIP, retrotransposon expression analysis, in vivo mouse models Nature communications High 37454216
2021 PHF8 regulates key synaptic genes in astrocytes by maintaining low levels of H4K20me3. PHF8 has a regulatory crosstalk with Notch signaling to balance expression of the master astrocytic gene Nfia. PHF8 depletion in astrocytes impairs neuronal synapse formation and maturation in vitro. Genome-wide analyses (ChIP-seq), siRNA knockdown, co-culture neuronal synapse assay, biochemical assays Development (Cambridge, England) Medium 34081130
2020 PHF8 transcriptionally upregulates FOXA2 by demethylating and removing repressive histone markers (H3K9me1/2, H4K20me1) on the FOXA2 gene promoter. Elevated FOXA2 subsequently regulates gene expression programs required for neuroendocrine prostate cancer (NEPC) development. Animals without Phf8 (KO) failed to develop NEPC in TRAMP mouse model. Phf8 KO mice (TRAMP model), ChIP (PHF8 and histone marks at FOXA2 promoter), gene expression analysis, PDX models The Journal of pathology High 33009820
2019 PHF8 interacts with U1 spliceosomal proteins including SRPK1 and snRNP70 (identified by immunoprecipitation). PHF8 controls inclusion of HLA-G intron 4 and is associated with RNAPII accumulation at this intron. PHF8 knockdown generates the immunosuppressive alternative splice product soluble HLA-G in endothelial cells. Co-IP (PHF8-SRPK1/snRNP70), ChIP (RNAPII and H3K9 marks), RT-PCR splice assay, angiogenic sprouting assay FEBS letters Medium 30758047
2024 PHF8 demethylates transcription factor YY1 (a non-histone substrate), functioning as a co-repressor for nuclear-coded ETC (electron transport chain) genes, thereby driving mitochondrial ROS production and cancer cell growth. Pharmacological inhibition of PHF8 with a specific inhibitor (iPHF8) regulates YY1 methylation, ETC gene transcription, mROS production, and cancer cell growth in colon and lung cancer. Demethylase assay (non-histone substrate YY1), pharmacological inhibitor (iPHF8), ChIP, gene expression, cell-line/PDX xenograft Proceedings of the National Academy of Sciences of the United States of America High 38165927
2022 PHF8 regulates TGFβ signaling pathway transcriptionally and epigenomically. PHF8 requires its histone demethylase activity to enhance melanoma cell invasion. PHF8 promotes dissemination but not subcutaneous tumor growth in vivo. Loss- and gain-of-function (KO and overexpression), transcriptomic and epigenomic (ChIP-seq) analyses, invasion assays, in vivo mouse dissemination model Science advances Medium 35179962
2020 PHF8 interacts with c-Jun on the PRKCA (PKCα) promoter to regulate its transcription. PHF8 depletion greatly upregulates PTEN expression. The mechanism involves the PHF8-regulated PKCα-Src axis, which destabilizes PTEN. PHF8 and PKCα show positive correlation in gastric cancer tissues, both negatively correlating with PTEN. Co-IP (PHF8-c-Jun), ChIP (PHF8 and histone marks at PRKCA promoter), microarray, PTEN expression rescue assay Proceedings of the National Academy of Sciences of the United States of America Medium 32958674
2022 NEDD4L (E3 ubiquitin ligase) interacts with PHF8 and induces its degradation via ubiquitination. PHF8 limits enrichment of H3K9me2 at the ATF2 promoter, enhancing ATF2 transcription. NEDD4L-mediated PHF8 degradation thus suppresses ATF2-driven prostate cancer cell proliferation. Co-IP (NEDD4L-PHF8), ubiquitination assay, ChIP, knockdown/overexpression Clinical & translational oncology Medium 36136271
2023 PHF8 forms a complex with c-MYC and upregulates TEAD1 in a histone demethylation-dependent manner. TEAD1 transcriptionally upregulates GLUL (glutamate-ammonia ligase), which promotes lipid deposition and ccRCC progression. PHF8 is regulated by the VHL/HIF axis. CRISPR-Cas9 screen, Co-IP (PHF8-c-MYC), ChIP, gene expression analysis, in vitro/in vivo functional assays Science advances Medium 37531433
2024 PHF8 concentrates at laser-induced DNA damage tracks in a DYRK1B-dependent manner. PHF8 is the major demethylase that reverses H3K9me2 laid down by the DYRK1B-EHMT2 pathway at DSBs, promoting timely resumption of transcription. PHF8 also assists recovery of rDNA transcription following nucleolar DSB repair. Live cell imaging (laser damage tracks), ChIP, siRNA/genetic knockdown, transcription recovery assays Nucleic acids research Medium 39087553
2023 PHF8 promotes hepatocellular carcinoma by transcriptionally upregulating FIP200-dependent autophagy (via demethylation at FIP200/SNAI1/VIM promoters), leading to autophagic degradation of E-cadherin and EMT. PHF8 regulates SNAI1, VIM, and FIP200 transcription but does not directly regulate N-cadherin or E-cadherin transcription. ChIP, knockdown/overexpression, autophagy flux assay (mCherry-GFP-LC3), rescue experiments, xenograft Journal of experimental & clinical cancer research Medium 30180906
2017 JMJD-1.2 (PHF8 C. elegans homolog) catalytic activity is required non-cell-autonomously for proper axon guidance. Loss of JMJD-1.2 dysregulates transcription of Hedgehog-related genes wrt-8 and grl-16. Overexpression of wrt-8 or grl-16 is sufficient to induce axonal defects, and these act on axon guidance through actin remodelers. C. elegans genetics (loss of function, overexpression), epistasis analysis, transcriptional analysis Development (Cambridge, England) Medium 28126843
2023 PHF8 inhibition promotes proteasomal degradation of H3K9 methyltransferase SETDB1 in a demethylase-independent manner, leading to H3K9me3 reduction and retrotransposon de-repression. This mechanism is distinct from PHF8's histone demethylase activity. CRISPR KO, proteasome inhibitor assays, ChIP (H3K9me3 and retrotransposons), western blot (SETDB1 levels) Nature communications Medium 37454216
2025 PHF8 (KDM7B) is the bona fide RNF113A demethylase, establishing a reversible non-histone methylation event. KDM7B antagonizes SMYD3 by maintaining low levels of methylated RNF113A, thereby limiting ASCC activation and sensitizing cancer cells to alkylating agents. High KDM7B levels correlate with improved SCLC patient prognosis. In vitro demethylase assay (RNF113A as substrate), CRISPR on/off modulation in SCLC mouse models, xenograft drug response studies bioRxivpreprint Medium 41509214
2026 PHF8 is a key driver of the serine biosynthesis pathway in neural stem cells, safeguarding the intracellular serine pool for neural progenitor proliferation. PHF8 fine-tunes chromatin accessibility at promoters of metabolic genes. Loss of PHF8 disrupts amino acid metabolism, blocks autophagy, impairs vesicle formation, causes replication defects, DNA damage, and proliferation arrest. In vivo PHF8 deficiency halts neurogenesis, progenitor expansion, and neuron generation in developing mouse embryo brains. Multi-omics (transcriptomics, epigenomics/ATAC-seq, metabolomics), Phf8 conditional KO mice, serine pathway gene expression/ChIP analysis EMBO reports Medium 41714361
2026 Znf711-Phf8 complex operates as a repressive unit in neutrophil development: Znf711 sequesters Phf8, preventing its recruitment by Gfi1 to the c/ebpα promoter. Upon Znf711 loss, Phf8 is recruited by Gfi1 to the c/ebpα promoter where SUMOylated Phf8 acts as a corepressor to inhibit c/ebpα transcription. C/ebpα directly activates znf711 expression, creating a positive feedback loop. Loss/gain-of-function experiments, Co-IP (Znf711-Phf8; Gfi1-Phf8), ChIP (Phf8 at c/ebpα promoter), SUMO modification assays, gene expression Haematologica Medium 41709745
2025 PHF8 interacts with KDM2A via two regions including one containing an intrinsically disordered region (IDR). PHF8-KDM2A interaction is regulated by phosphorylation status of KDM2A at Ser731. Dephosphorylation of KDM2A-Ser731 (by AMPK activation) decreases binding to PHF8, activating KDM2A to reduce rRNA transcription. The PHF8-KDM2A interaction controls rRNA transcription and cell proliferation. Co-IP (PHF8-KDM2A), mutagenesis (Ser731Ala), AMPK activator treatment, rRNA transcription reporter, cell proliferation assay Biomolecules Medium 40427554
2023 Computational analysis of PHF8 catalytic mechanism reveals that dioxygen binding in PHF8 requires a transition from off-line to in-line 2-oxoglutarate coordination mode (unlike ethylene-forming enzyme), and that it is the protein environment that controls formation of the in-line FeIII-OO·- intermediate required for H3K9me2 hydroxylation and demethylation. QM/MM molecular dynamics, QM/MM metadynamics simulations, classical MD Chemistry (Weinheim an der Bergstrasse, Germany) Low 36701641

Source papers

Stage 0 corpus · 90 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2010 PHF8 mediates histone H4 lysine 20 demethylation events involved in cell cycle progression. Nature 341 20622854
2010 Histone H4K20/H3K9 demethylase PHF8 regulates zebrafish brain and craniofacial development. Nature 247 20622853
2010 PHF8 activates transcription of rRNA genes through H3K4me3 binding and H3K9me1/2 demethylation. Nature structural & molecular biology 179 20208542
2010 A functional link between the histone demethylase PHF8 and the transcription factor ZNF711 in X-linked mental retardation. Molecular cell 177 20346720
2016 Stabilization of histone demethylase PHF8 by USP7 promotes breast carcinogenesis. The Journal of clinical investigation 170 27183383
2005 Mutations in PHF8 are associated with X linked mental retardation and cleft lip/cleft palate. Journal of medical genetics 170 16199551
2009 PHF8, a gene associated with cleft lip/palate and mental retardation, encodes for an Nepsilon-dimethyl lysine demethylase. Human molecular genetics 132 19843542
2011 Systematic knockdown of epigenetic enzymes identifies a novel histone demethylase PHF8 overexpressed in prostate cancer with an impact on cell proliferation, migration and invasion. Oncogene 97 22120715
2010 PHF8 targets histone methylation and RNA polymerase II to activate transcription. Molecular and cellular biology 91 20421419
2010 The X-linked mental retardation gene PHF8 is a histone demethylase involved in neuronal differentiation. Cell research 85 20548336
2007 A novel mutation in the PHF8 gene is associated with X-linked mental retardation with cleft lip/cleft palate. Clinical genetics 84 17594395
2010 PHF8 is a histone H3K9me2 demethylase regulating rRNA synthesis. Cell research 80 20531378
2007 Screening of mutations in the PHF8 gene and identification of a novel mutation in a Finnish family with XLMR and cleft lip/cleft palate. Clinical genetics 75 17661819
2013 The histone demethylase PHF8 governs retinoic acid response in acute promyelocytic leukemia. Cancer cell 69 23518351
2017 Histone demethylase PHF8 promotes epithelial to mesenchymal transition and breast tumorigenesis. Nucleic acids research 63 27899639
2010 Structural insights into a novel histone demethylase PHF8. Cell research 62 20101266
2018 Phf8 histone demethylase deficiency causes cognitive impairments through the mTOR pathway. Nature communications 53 29317619
2020 Histone demethylase PHF8 drives neuroendocrine prostate cancer progression by epigenetically upregulating FOXA2. The Journal of pathology 52 33009820
2016 c-MYC drives histone demethylase PHF8 during neuroendocrine differentiation and in castration-resistant prostate cancer. Oncotarget 51 27689328
2016 The HIF/PHF8/AR axis promotes prostate cancer progression. Oncogenesis 51 27991916
2013 Oncogenic features of PHF8 histone demethylase in esophageal squamous cell carcinoma. PloS one 49 24146981
2018 PHF8 upregulation contributes to autophagic degradation of E-cadherin, epithelial-mesenchymal transition and metastasis in hepatocellular carcinoma. Journal of experimental & clinical cancer research : CR 44 30180906
2014 The histone demethylase PHF8 is an oncogenic protein in human non-small cell lung cancer. Biochemical and biophysical research communications 44 25065740
2013 The G2/M regulator histone demethylase PHF8 is targeted for degradation by the anaphase-promoting complex containing CDC20. Molecular and cellular biology 42 23979597
2017 Phf8 loss confers resistance to depression-like and anxiety-like behaviors in mice. Nature communications 37 28485378
2012 The histone demethylase PHF8 is essential for cytoskeleton dynamics. Nucleic acids research 34 22850744
2010 Crystal structure of the PHF8 Jumonji domain, an Nepsilon-methyl lysine demethylase. FEBS letters 31 20067792
2017 Histone demethylase PHF8 accelerates the progression of colorectal cancer and can be regulated by miR-488 in vitro. Molecular medicine reports 29 28765946
2022 The histone demethylase PHF8 regulates TGFβ signaling and promotes melanoma metastasis. Science advances 28 35179962
2020 Contribution of synergism between PHF8 and HER2 signalling to breast cancer development and drug resistance. EBioMedicine 28 31923801
2019 Aluminium-induced synaptic plasticity injury via the PHF8-H3K9me2-BDNF signalling pathway. Chemosphere 28 31835052
2020 Targeting the histone demethylase PHF8-mediated PKCα-Src-PTEN axis in HER2-negative gastric cancer. Proceedings of the National Academy of Sciences of the United States of America 27 32958674
2020 The role of PHF8 and TLR4 in osteogenic differentiation of periodontal ligament cells in inflammatory environment. Journal of periodontology 27 33040333
2015 The histone demethylase PHF8 represses cardiac hypertrophy upon pressure overload. Experimental cell research 27 25921086
2014 Cyclin E-CDK2 protein phosphorylates plant homeodomain finger protein 8 (PHF8) and regulates its function in the cell cycle. The Journal of biological chemistry 27 25548279
2023 Loss of PHF8 induces a viral mimicry response by activating endogenous retrotransposons. Nature communications 26 37454216
2017 PIP2 epigenetically represses rRNA genes transcription interacting with PHF8. Biochimica et biophysica acta. Molecular and cell biology of lipids 25 29246768
2016 The Histone Demethylase PHF8 Is Essential for Endothelial Cell Migration. PloS one 25 26751588
2023 PHF8-GLUL axis in lipid deposition and tumor growth of clear cell renal cell carcinoma. Science advances 24 37531433
2015 The histone demethylase PHF8 promotes prostate cancer cell growth by activating the oncomiR miR-125b. OncoTargets and therapy 24 26309412
2021 PHF8-promoted TOPBP1 demethylation drives ATR activation and preserves genome stability. Science advances 21 33952527
2016 Proteomic dissection of LPS-inducible, PHF8-dependent secretome reveals novel roles of PHF8 in TLR4-induced acute inflammation and T cell proliferation. Scientific reports 21 27112199
2022 Variants in PHF8 cause a spectrum of X-linked neurodevelopmental disorders and facial dysmorphology. HGG advances 20 35469323
2017 JMJD-1.2/PHF8 controls axon guidance by regulating Hedgehog-like signaling. Development (Cambridge, England) 20 28126843
2014 PHD finger protein 2 (PHF2) represses ribosomal RNA gene transcription by antagonizing PHF finger protein 8 (PHF8) and recruiting methyltransferase SUV39H1. The Journal of biological chemistry 20 25204660
2017 Histone demethylase PHF8 promotes progression and metastasis of gastric cancer. American journal of cancer research 19 28401003
2024 Targeting the PHF8/YY1 axis suppresses cancer cell growth through modulation of ROS. Proceedings of the National Academy of Sciences of the United States of America 18 38165927
2023 Homocysteine metabolites inhibit autophagy, elevate amyloid beta, and induce neuropathy by impairing Phf8/H4K20me1-dependent epigenetic regulation of mTOR in cystathionine β-synthase-deficient mice. Journal of inherited metabolic disease 17 37477632
2019 PHF8 Plays an Oncogene Function in Hepatocellular Carcinoma Formation. Oncology research 17 30764899
2018 The histone demethylase PHF8 promotes adult acute lymphoblastic leukemia through interaction with the MEK/ERK signaling pathway. Biochemical and biophysical research communications 17 29330049
2017 The histone demethylase PHF8 is a molecular safeguard of the IFNγ response. Nucleic acids research 17 28100697
2022 NEDD4L represses prostate cancer cell proliferation via modulating PHF8 through the ubiquitin-proteasome pathway. Clinical & translational oncology : official publication of the Federation of Spanish Oncology Societies and of the National Cancer Institute of Mexico 16 36136271
2017 Histone demethylase PHF8 regulates hypoxia signaling through HIF1α and H3K4me3. Biochimica et biophysica acta. Gene regulatory mechanisms 16 28734980
2023 Dioxygen Binding Is Controlled by the Protein Environment in Non-heme FeII and 2-Oxoglutarate Oxygenases: A Study on Histone Demethylase PHF8 and an Ethylene-Forming Enzyme. Chemistry (Weinheim an der Bergstrasse, Germany) 14 36701641
2020 CK2 kinase-mediated PHF8 phosphorylation controls TopBP1 stability to regulate DNA replication. Nucleic acids research 14 33010150
2024 PHF8/KDM7B: A Versatile Histone Demethylase and Epigenetic Modifier in Nervous System Disease and Cancers. Epigenomes 13 39311138
2020 MicroRNA-383 inhibits proliferation, migration, and invasion in hepatocellular carcinoma cells by targeting PHF8. Molecular genetics & genomic medicine 13 32441881
2015 A PHF8 homolog in C. elegans promotes DNA repair via homologous recombination. PloS one 13 25853498
2025 Genome-wide CRISPR screening identifies PHF8 as an effective therapeutic target for KRAS- or BRAF-mutant colorectal cancers. Journal of experimental & clinical cancer research : CR 11 40001243
2021 The histone demethylase PHF8 regulates astrocyte differentiation and function. Development (Cambridge, England) 11 34081130
2021 Histone demethylase PHF8 promotes cell growth and metastasis of non-small-cell lung cancer through activating Wnt/β-catenin signaling pathway. Histology and histopathology 10 34100557
2020 MYC Regulates PHF8, Which Promotes the Progression of Gastric Cancer by Suppressing miR-22-3p. Technology in cancer research & treatment 9 33111613
2022 Disrupting PHF8-TOPBP1 connection elicits a breast tumor-specific vulnerability to chemotherapeutics. Cancer letters 8 35051531
2022 Histone demethylase KDM3C regulates the lncRNA GAS5-miR-495-3p-PHF8 axis in cardiac hypertrophy. Annals of the New York Academy of Sciences 8 35777757
2019 The histone demethylase PHF8 facilitates alternative splicing of the histocompatibility antigen HLA-G. FEBS letters 7 30758047
2016 [The pilot study on the expression of PHF8, H3K9me2, BDNF and LTP in the hippocampus of rats exposed to aluminum]. Zhonghua lao dong wei sheng zhi ye bing za zhi = Zhonghua laodong weisheng zhiyebing zazhi = Chinese journal of industrial hygiene and occupational diseases 7 27014810
2025 hnRNPA2B1 drives colorectal cancer progression via the circCDYL/EIF4A3/PHF8 axis. The Kaohsiung journal of medical sciences 6 39810713
2024 PHF8 facilitates transcription recovery following DNA double-strand break repair. Nucleic acids research 6 39087553
2023 Functional Characterization of a Phf8 Processed Pseudogene in the Mouse Genome. Genes 6 36672913
2017 Structure-Based Design of a New Scaffold for Cell-Penetrating Peptidic Inhibitors of the Histone Demethylase PHF8. Chembiochem : a European journal of chemical biology 6 28430394
2024 Homocysteine metabolites impair the PHF8/H4K20me1/mTOR/autophagy pathway by upregulating the expression of histone demethylase PHF8-targeting microRNAs in human vascular endothelial cells and mice. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 5 39323294
2023 Dioxygen Binding Is Controlled by the Protein Environment in Non-heme FeII and 2-Oxoglutarate Oxygenases: A Study on Histone Demethylase PHF8 and an Ethylene-Forming Enzyme. Chemistry (Weinheim an der Bergstrasse, Germany) 5 37009811
2022 PHF8 promotes osteogenic differentiation of BMSCs in old rat with osteoporosis by regulating Wnt/β-catenin pathway. Open life sciences 5 36518887
2025 Long-term exposure to environmentally relevant concentrations of hexafluoropropylene oxide dimer acid (GenX) induces trans-generational motor deficits through H3K27 demethylase jmjd-1.2 /PHF8 in Caenorhabditis elegans. Environmental pollution (Barking, Essex : 1987) 4 40803444
2025 Histone Demethylase PHF8 Confers Protection against Oxidative Stress and Cardiomyocyte Apoptosis in Heart Failure by Upregulating FOXA2. International heart journal 3 39894540
2024 Transcription factor Olig2 is a major downstream effector of histone demethylase Phf8 during oligodendroglial development. Glia 3 38613395
2024 Role and mechanism of histone demethylase PHF8 in weightlessness osteoporosis. Experimental cell research 3 39389337
2023 Histone demethylase PHF8 facilitates the development of chronic myeloid leukaemia by directly targeting BCR::ABL1. British journal of haematology 3 37469124
2020 Histone Demethylase PHF8 Is Required for the Development of the Zebrafish Inner Ear and Posterior Lateral Line. Frontiers in cell and developmental biology 3 33330448
2024 Insights into the Dissociation Process and Binding Pattern of the BRCT7/8-PHF8 Complex. ACS omega 2 38764655
2024 Histone demethylase PHF8 protected against chondrocyte injury and alleviated posttraumatic osteoarthritis by epigenetically enhancing WWP2 expression. Human & experimental toxicology 2 39454680
2023 Expression Patterns of PAK4 and PHF8 Are Associated with the Survival of Gallbladder Carcinoma Patients. Diagnostics (Basel, Switzerland) 2 36980457
2023 LncSUMO1P3 exacerbates malignant behaviors of esophageal squamous cell carcinoma cells via miR-486-5p/PHF8/CD151. Heliyon 2 37809985
2025 Interaction Between PHF8 and a Segment of KDM2A, Which Is Controlled by the Phosphorylation Status at a Specific Serine in an Intrinsically Disordered Region of KDM2A, Regulates rRNA Transcription and Cell Proliferation in a Breast Cancer Cell Line. Biomolecules 1 40427554
2025 HER3 promotes triple-negative breast cancer progression by upregulating PHF8 via miR-34b-5p-dependent mechanism. Cell death & disease 1 41198671
2023 A Proteome-Wide Effect of PHF8 Knockdown on Cortical Neurons Shows Downregulation of Parkinson's Disease-Associated Protein Alpha-Synuclein and Its Interactors. Biomedicines 1 36831023
2026 KDM7B-mediated demethylation of RNF113A regulates small cell lung cancer sensitivity to alkylation damage. bioRxiv : the preprint server for biology 0 41509214
2026 The Znf711-Phf8 complex functions as a transcriptional rheostat essential for neutrophil development. Haematologica 0 41709745
2026 Epigenetic regulation of serine biosynthesis by PHF8 during neurogenesis. EMBO reports 0 41714361
2026 Targeting the circC16orf62/miR-1299/PHF8 axis to suppress metastasis and overcome immune evasion in triple-negative breast cancer. Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie 0 42008953

Missed literature

Know a paper Affinage missed for PHF8? Flag it for the maintainers and the community.

No submissions yet.